ABSTRACT Opioid misuse/abuse remains at unprecedented levels and is a major public health burden. Stress-reactivity interferes with opioid abstinence and increase risks of relapse and adverse outcomes. We have shown that the pharmacological stressor yohimbine + hydrocortisone (YOH/CORT) increases opioid seeking in buprenorphine (BUP)-stabilized volunteers. Prior studies suggest maintenance on methadone (MTD) and BUP can attenuate stress-reactivity, but those studies have several limitations. BUP is effective via opioid substitution (withdrawal suppression) and cross-tolerance (blockade); another important but poorly understood mechanism is that BUP might afford stress-protection. In our studies, reactivity to YOH/CORT (which co-activates noradrenaline and glucocorticoid systems) was found for some measures but not others; this suggests moderate-dose BUP has a partial blocking effect on stress reactivity. Although stress plays a role in drug seeking/relapse, one research gap is that no studies have examined whether BUP (or MTD) dose-dependently attenuates stress reactivity in subjects with opioid use disorder. Improving treatment outcomes requires that we identify opioid-abusing patients with elevated relapse risk to address their susceptibility. Yet, few studies have examined whether chronic stress biomarker levels or acute stress-reactivity predicts relapse and consequences in subjects with opioid use disorder. In this project, we will determine whether maintenance on varying buprenorphine/naloxone (BUP/NAL) doses reduces YOH/CORT dose-related reactivity (phase 1: within-subject crossover), then use these data to predict opioid relapse and consequences during a standardized outpatient BUP/NAL dose taper paired with opioid abstinence-contingent reinforcement, and at 1, 2 and 3 months follow up (phase 2: intent-to- treat). We predict: (1a) YOH/CORT will increase opioid price-inelasticity (greater economic demand), elevate acute stress biomarkers (e.g. blood pressure, plasma noradrenaline, saliva cortisol, negative mood) and novel indices predicted to be sensitive based on non-opioid studies (e.g. blood levels of BDNF and pro-inflammatory cytokines; saliva ?-amylase); (1b) BUP/NAL will dose-dependently block YOH/CORT stress-reactivity; (2a) stress-reactivity at lower-dose BUP/NAL will predict more opioid use and adverse consequences during and after BUP/NAL dose tapering; and chronic stress indices (e.g. hair cortisol level, questionnaire responses) will modulate YOH/CORT reactivity (1c) and relapse (2b). Impact of this project will be exceptional because: opioid use problems remain at critical levels and stress-related opioid use is poorly understood, posing a major clinical challenge; the highly innovative idea that BUP affords stress protection will be tested using rigorous methods (placebo controlled, dose-response drug-interaction design) with established and novel biomarkers, and mediators/moderators of stress-reactivity will be used to predict relapse potential to bridge a large translational gap. This project offers a novel template to examine effects of stressors on drug seeking and relapse biomarkers, and to develop treatment approaches to reduce stress-potentiated drug use.